(M-037) A quantitative systems pharmacology model of felzartamab, an anti-CD38 antibody, to link immune cell and pharmacodynamic responses in immune mediated diseases
Senior Scientist, Clinical Biomarkers Biogen, United States
Disclosure(s):
Millie Shah: No relevant disclosure to display
Enter your core abstract text here using the suggested layout. Abstracts are text only: No figures/tables. Do not paste author or affiliation information in the body of your abstract. Max character count not including spaces for abstract body is 2800.: Felzartamab is a fully human immunoglobulin G1 monoclonal antibody that targets and depletes cells with high surface expression of CD38. Terminally differentiated plasma cells and plasmablasts highly express CD38 and are the main source of pathogenic antibodies in immune-mediated diseases (IMDs). Natural killer (NK) cells also express CD38 and are thought to contribute to inflammatory disease. Clinical trials across IMDs have shown therapeutic benefit following felzartamab treatment. This study aimed to further characterize the relationship between drug-mediated cellular depletion, homeostatic generation of new target cells, and downstream pharmacodynamic (PD) effects. Here we describe a multi-compartment mechanistic model to better understand the impact of cellular turnover on felzartamab drug effects and PD durability.
A five-compartment model was established that includes a central compartment, a peripheral compartment, and compartments for antibody secreting cell maturation and survival (immunologic, bone marrow, and gut). The model encodes maturation of naive B cells into plasma cells, secretion of immunoglobulin A (IgA) and immunoglobulin G (IgG), and drug-dependent killing of CD38+ plasma cells and NK cells. Felzartamab exposure was modeled using parameters derived from a previously developed population pharmacokinetic model. The model was parameterized using flow cytometry and immunoglobulin data collected in 4 felzartamab clinical trials across multiple IMD indications (primary membranous nephropathy [NCT04145440 and NCT04733040]1, IgA nephropathy [NCT05065970], and antibody-mediated rejection [NCT05021484]2).
The model was able to capture reduction and repopulation of circulating short-lived plasma cells and NK cells following felzartamab treatment, consistent with observed trends in clinical data. Model simulations suggest that target cell half-life is an important determinant of the magnitude of cellular depletion as well as the durability of PD effects. In addition, the model recapitulates the differences observed in serum IgG and IgA dynamics following treatment. Serum IgG titers were reduced to a lesser extent than serum IgA titers and recovered to baseline following the last dose of felzartamab. In contrast, serum IgA titers remained below baseline and exhibited slower recovery. Simulations suggest that the biophysical compartment of IgG and IgA secreting cells could contribute to the observed differences in serum IgG and IgA dynamics. Further experimental studies are needed to validate the possible contribution of IgA vs IgG cell survival niche, compartmental drug activity, and cell half-life to differential immunoglobulin dynamics. Taken together, the model identified potential target cell characteristics important to understanding felzartamab drug effects.
A quantitative systems pharmacology model was developed to link the mechanistic effects of felzartamab on plasma and NK cells to cellular regeneration and PD effects (immunoglobulin secretion). Model insights suggest that CD38+ target cell characteristics are important for understanding felzartamab effects, and further studies are needed to profile pathogenic target cells in immune mediated diseases.
Citations: [1]Rovin BH, Ronco PM, Wetzels JFM, et al. Phase 1b/2a Study Assessing the Safety and Efficacy of Felzartamab in Anti-Phospholipase A2 Receptor Autoantibody-Positive Primary Membranous Nephropathy. Kidney Int Rep. 2024;9(9):2635-2647. Published 2024 Jun 20. doi:10.1016/j.ekir.2024.06.018 [2] Mayer KA, Schrezenmeier E, Diebold M, et al. A Randomized Phase 2 Trial of Felzartamab in Antibody-Mediated Rejection. N Engl J Med. 2024;391(2):122-132. doi:10.1056/NEJMoa2400763
